Project summary The overdose epidemic in the United States has followed an exponential curve since 1979 with no sign of abating. On the contrary, a series of political, economic and technological factors are fueling drug use epidemics in the country. Technological advances have led to an explosion in the emergence of powerful synthetic substances which can be produced with minimal equipment. Inequalities, poor mental health services and other social issues contribute to an increased susceptibility to drug use disorders. Improved transport and communication infrastructure, including the internet, facilitates the emergence of drug markets. As a result, polysubstance use is diversifying presenting new health risks and new challenges for treatment. In 2017, over 70,000 people died of an overdose and HIV outbreaks were identified in two cities of Massachusetts. Curbing these alarming trends requires preemptive epidemic preparedness and the latter should be based on a rigorous and systematic assessment of the factors influencing drug use epidemics. These factors, however, are dynamic and interacting. We will use an emerging infectious disease framework and dynamic mathematical modeling methods to predict emerging drug use epidemics in the United States. Mathematical modeling has been used extensively to forecast emerging and re- emerging infectious disease epidemics because it allows to mechanistically represent the different factors determining disease transmission and their dynamics over time. We will develop a mathematical model of drug use in the United States which represents current patterns of drug use across the country and associated HIV, HCV and overdose incidence. It will explicitly represent heterogeneity in susceptibility to drug use disorders in the population, social networks and the influence of drug markets, law enforcement and healthcare services on drug use and associated health outcomes. This project will 1) systematically investigate the potential for emerging drug use epidemics; 2) identify the optimal allocation of resources towards combination of interventions to control them and limit associated harms and 3) pilot a targeted mass-media based intervention to increase access to appropriate prevention methods among a specific population at risk of an emerging drug use in real time as identified by the model. This project has the potential to significantly improve our public health response to emerging drug use epidemics and to reduce their toll on the health of the United States population.